NKCC1: Newly Found as a Human Disease-Causing Ion Transporter

Koumangoye, Rainelli; Bastarache, Lisa; Delpire, Eric

doi:10.1093/function/zqaa028

Cited by 38 publications

(38 citation statements)

References 134 publications

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“…NKCC1 deletion is tolerated, however, apparently through upregulation of other (non-SLC12A) transporter activities 72 . Consistent with previous reports 70,72 , NKCC1 −/− mice showed obvious growth and developmental defects (small size, deaf, unsteady gait) and weaned in non-Mendelian ratios. Fibroblasts derived from adult PER2::LUC NKCC1 −/− mice had significantly reduced cellular Na + and K + levels with commensurately increased soluble and total protein levels (Supplementary Fig.…”

Section: Resultssupporting

confidence: 92%

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Compensatory ion transport buffers daily protein rhythms to regulate osmotic balance and cellular physiology

et al. 2021

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Between 6–20% of the cellular proteome is under circadian control and tunes mammalian cell function with daily environmental cycles. For cell viability, and to maintain volume within narrow limits, the daily variation in osmotic potential exerted by changes in the soluble proteome must be counterbalanced. The mechanisms and consequences of this osmotic compensation have not been investigated before. In cultured cells and in tissue we find that compensation involves electroneutral active transport of Na+, K+, and Cl− through differential activity of SLC12A family cotransporters. In cardiomyocytes ex vivo and in vivo, compensatory ion fluxes confer daily variation in electrical activity. Perturbation of soluble protein abundance has commensurate effects on ion composition and cellular function across the circadian cycle. Thus, circadian regulation of the proteome impacts ion homeostasis with substantial consequences for the physiology of electrically active cells such as cardiomyocytes.

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Section: Resultssupporting

confidence: 92%

“…The SLC12A family includes nine members (including KCC1-4) whose overlapping and semi-redundant functions are important for physiological function and overall viability 37,70,71 . The same is true for the four WNK paralogs, as well as OSXR1 with SPAK1 31,69 .…”

Section: Resultsmentioning

confidence: 99%

Compensatory ion transport buffers daily protein rhythms to regulate osmotic balance and cellular physiology

et al. 2021

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“…Na-K-Cl cotransporter-1 (NKCC1) and aquaporin 5 (AQP5) are common markers of SGECs and their expression are closely linked to changes in salivary gland activity. 26 27 Immunofluorescent imaging showed decreased expression of NKCC1 ( figure 6A ) and AQP5 ( online supplemental S-Figure 8A ) proteins in submandibular glands of LAMP3 mice compared with control mice cannulated with a vector encoding GFP. Expression of NKCC1 ( figure 6B ) and AQP5 ( online supplemental S-Figure 8B ) was significantly decreased in LAMP3 mice 6 months after transduction compared with GFP control mice and 2 months LAMP3 mice.…”

Section: Resultsmentioning

confidence: 97%

Lysosome-associated membrane protein 3 misexpression in salivary glands induces a Sjögren’s syndrome-like phenotype in mice

et al. 2021

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ObjectivesSjögren’s syndrome (SS) is an autoimmune sialadenitis with unknown aetiology. Although extensive research implicated an abnormal immune response associated with lymphocytes, an initiating event mediated by salivary gland epithelial cell (SGEC) abnormalities causing activation is poorly characterised. Transcriptome studies have suggested alternations in lysosomal function are associated with SS, but a cause and effect linkage has not been established. In this study, we demonstrated that altered lysosome activity in SGECs by expression of lysosome-associated membrane protein 3 (LAMP3) can initiate an autoimmune response with autoantibody production and salivary dysfunction similar to SS.MethodsRetroductal cannulation of the submandibular salivary glands with an adeno-associated virus serotype 2 vector encoding LAMP3 was used to establish a model system. Pilocarpine-stimulated salivary flow and the presence of autoantibodies were assessed at several time points post-cannulation. Salivary glands from the mice were evaluated using RNAseq and histologically.ResultsFollowing LAMP3 expression, saliva flow was significantly decreased and serum anti-Ro/SSA and La/SSB antibodies could be detected in the treated mice. Mechanistically, LAMP3 expression increased apoptosis in SGECs and decreased protein expression related to saliva secretion. Analysis of RNAseq data suggested altered lysosomal function in the transduced SGECs, and that the cellular changes can chemoattract immune cells into the salivary glands. Immune cells were activated via toll-like receptors by damage-associated molecular patterns released from LAMP3-expressing SGECs.ConclusionsThese results show a critical role for lysosomal trafficking in the development of SS and establish a causal relationship between LAMP3 misexpression and the development of SS.

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“…Distinct glial [Cl – ] int might thus affect inhibitory synaptic transmission in these two brain regions. There is an increasing number of human diseases that are associated with altered intracellular chloride homeostasis ( Uyanik et al, 2006 ; Kourdougli et al, 2017 ; Flores et al, 2019 ; Auer et al, 2020 ; Chivukula et al, 2020 ; Kovermann et al, 2020 ; Koumangoye et al, 2021 ). Our results suggest that changes in transporter function/expression will have different consequences in separate brain regions.…”

Section: Discussionmentioning

confidence: 99%

Glial Chloride Homeostasis Under Transient Ischemic Stress

Engels

Kalia

Rahmati

et al. 2021

Front. Cell. Neurosci.

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High water permeabilities permit rapid adjustments of glial volume upon changes in external and internal osmolarity, and pathologically altered intracellular chloride concentrations ([Cl–]int) and glial cell swelling are often assumed to represent early events in ischemia, infections, or traumatic brain injury. Experimental data for glial [Cl–]int are lacking for most brain regions, under normal as well as under pathological conditions. We measured [Cl–]int in hippocampal and neocortical astrocytes and in hippocampal radial glia-like (RGL) cells in acute murine brain slices using fluorescence lifetime imaging microscopy with the chloride-sensitive dye MQAE at room temperature. We observed substantial heterogeneity in baseline [Cl–]int, ranging from 14.0 ± 2.0 mM in neocortical astrocytes to 28.4 ± 3.0 mM in dentate gyrus astrocytes. Chloride accumulation by the Na+-K+-2Cl– cotransporter (NKCC1) and chloride outward transport (efflux) through K+-Cl– cotransporters (KCC1 and KCC3) or excitatory amino acid transporter (EAAT) anion channels control [Cl–]int to variable extent in distinct brain regions. In hippocampal astrocytes, blocking NKCC1 decreased [Cl–]int, whereas KCC or EAAT anion channel inhibition had little effect. In contrast, neocortical astrocytic or RGL [Cl–]int was very sensitive to block of chloride outward transport, but not to NKCC1 inhibition. Mathematical modeling demonstrated that higher numbers of NKCC1 and KCC transporters can account for lower [Cl–]int in neocortical than in hippocampal astrocytes. Energy depletion mimicking ischemia for up to 10 min did not result in pronounced changes in [Cl–]int in any of the tested glial cell types. However, [Cl–]int changes occurred under ischemic conditions after blocking selected anion transporters. We conclude that stimulated chloride accumulation and chloride efflux compensate for each other and prevent glial swelling under transient energy deprivation.

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NKCC1: Newly Found as a Human Disease-Causing Ion Transporter

Cited by 38 publications

References 134 publications

Compensatory ion transport buffers daily protein rhythms to regulate osmotic balance and cellular physiology

Compensatory ion transport buffers daily protein rhythms to regulate osmotic balance and cellular physiology

Lysosome-associated membrane protein 3 misexpression in salivary glands induces a Sjögren’s syndrome-like phenotype in mice

Glial Chloride Homeostasis Under Transient Ischemic Stress

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